Edited by: Tsuguhito Ota, Kanazawa University, Japan
Reviewed by: Undurti N. Das, UND LIfe Sciences, USA; Marek Bolanowski, Wroclaw Medical University, Poland
*Correspondence: Jean-François Tanti, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Bâtiment Archimed, 151, route de St. Antoine de Ginestière, BP 2 3194, 06204, Nice Cedex 3, France. e-mail:
†Present address: Jennifer Jager, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
This article was submitted to Frontiers in Diabetes, a specialty of Frontiers in Endocrinology.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
Obesity is characterized by the development of a low-grade chronic inflammatory state in different metabolic tissues including adipose tissue and liver. This inflammation develops in response to an excess of nutrient flux and is now recognized as an important link between obesity and insulin resistance. Several dietary factors like saturated fatty acids and glucose as well as changes in gut microbiota have been proposed as triggers of this metabolic inflammation through the activation of pattern-recognition receptors (PRRs), including Toll-like receptors (TLR), inflammasome, and nucleotide oligomerization domain (NOD). The consequences are the production of pro-inflammatory cytokines and the recruitment of immune cells such as macrophages and T lymphocytes in metabolic tissues. Inflammatory cytokines activate several kinases like IKKβ, mTOR/S6 kinase, and MAP kinases as well as SOCS proteins that interfere with insulin signaling and action in adipocytes and hepatocytes. In this review, we summarize recent studies demonstrating that PRRs and stress kinases are important integrators of metabolic and inflammatory stress signals in metabolic tissues leading to peripheral and central insulin resistance and metabolic dysfunction. We discuss recent data obtained with genetically modified mice and pharmacological approaches suggesting that these inflammatory pathways are potential novel pharmacological targets for the management of obesity-associated insulin resistance.
Obesity is characterized by an excessive adipose tissue expansion due to an increase in nutrients intake and insufficient energetic expenditure. Obesity has dramatically increased worldwide and leads to numerous adverse metabolic disorders including cardiovascular diseases, type 2 diabetes, and some forms of cancer. Insulin resistance is associated with obesity and is a central component of type 2 diabetes, leading to altered glucose and lipid metabolism in adipose tissue, liver, and skeletal muscles. Insulin resistance is characterized by a decrease in insulin signaling mainly in the Insulin Receptor Substrate (IRS)/PI-3-kinase/PKB axis that is responsible for most of the metabolic actions of the hormone (Taniguchi et al.,
In this review, we will first describe the major mediators that link the excess of nutrients to the production of inflammatory cytokines, focusing on pattern-recognition receptors (PRRs). We will then discuss the intracellular signaling pathways activated by inflammatory mediators and involved in the desensitization of insulin signaling. We will also discuss whether and how the blockade of these mechanisms could improve insulin sensitivity.
Toll-like receptors (TLR) belong to the family of PRRs and play a crucial role in innate immunity by their ability to sense pathogens through the pathogen-associated molecular patterns (PAMPs) and to detect tissue injury through the danger-associated molecular patterns (DAMPs) (Mogensen,
Among the different members of the TLR family, several groups have reported a role for TLR2, TLR4 in inflammation and insulin resistance during obesity (Fresno et al.,
Saturated fatty acids are other potential ligands of TLR4 both in adipocytes and macrophages leading to the production of inflammatory cytokines and also ceramides (Shi et al.,
The
Tsukumo et al. | C3H/HeJ | 55 | ↓ | ↑ | = | ↓ | ↓ | ↑ | ↓ |
Poggi et al. | C3H/HeJ | 45 | = | = | ↓ | ↓ | = | ↑ | ↓ |
Suganami et al. | C3H/HeJ | 60 | = | ↑ | ND | ↓ | = | ND | ND |
Davis et al. | 10 ScN | 60 | ↓ | ↑ | ND | ↓ ± | ↓ | ND | ND |
Radin et al. | 10 ScN | 45 | ↓ | = | ↓ | ND | ND | ND | ↓ |
Li et al. | 10 ScN | 60 | ↓ | = | ND | ND | ND | ↓ | |
Shi et al. | TLR4−/− F | 60 | ↑ | ↑ | ↑ | ↓ | ↓ | ND | ND |
Shi et al. | TLR4−/− M | 60 | = | = | = | ↓ | ND | ND | ND |
Orr et al. | TLR4−/− | 45 | ↓ | = | ↓ | ↓ ± | ↑ M2 | ND | ↓ |
Saberi et al. | TLR4−/− | No data | ↓ | ND | ND | ND | ND | ND | ND |
Ding et al. | TLR4−/−LDLR−/− | 35.5 | = | = | = | = | = | ND | ND |
Kim et al. | TLR4−/− | 60 | = | ND | ND | ND | ND | ND | ND |
Saberi et al. | BMT-10ScN | No data | = | ↑ | = | ↓ | ↓ | ↑ | ↓ |
Orr et al. | BMT-TLR4−/− | 45 | = | = | ND | ↓ | ↑ M2 | ND | = |
Coenen et al. | BMT-TLR4−/− | 41 | = | = | ND | = | = | ND | ND |
Different studies have investigated the consequences of TLR4 invalidation specifically in immune cells by transplantation of bone marrow from TLR4-deficient mice into wild-type recipients. In one study, mice developed obesity but with less inflammation and insulin resistance in adipose tissue and liver and no change in muscles (Saberi et al.,
In summary, the consequences on weight gain and insulin resistance are different depending on the genetic background, the sex of the mice, the duration, and the lipid composition of the diet. In this regard, the percentage of saturated lipids in the diet could be important since the protection against insulin resistance seemed to occur selectively when the diet contained a high level of saturated lipids (Davis et al.,
TLR2 detects lipoproteins, lipoteichoic acid, and peptidoglycan from gram-positive bacteria and dimerizes with TLR1 and TLR6 (Mogensen,
Although the findings discussed above support a protective role of TLR2 inactivation in the context of obesity, a recent study reported that TLR2 knockout mice had a phenotype reminiscent of metabolic syndrome even on low-fat diet. In this setting, it was demonstrated that the gut microbiota was responsible for the development of insulin resistance (Caricilli et al.,
Nucleotide oligomerization domain (NOD) 1 and 2 are intracellular proteins that recognize cell wall peptidoglycan moieties from gram-negative or gram-positive bacteria, respectively (Mogensen,
Inflammasomes are multi-protein complexes composed of three proteins: the nucleotide-binding domain leucine-rich repeat (NLR) protein, the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) and the caspase-1. Four different inflammasomes have been identified so far namely NLRP1, NLRP3, NLRC4, and AIM2. Pathogen and danger-associated signals activate inflammasomes leading to the processing of IL-1β and IL-18 by caspase-1 (Mogensen,
The expression of NLRP3 and caspase-1 is increased in adipose tissue of obese mice, overweight subjects, or obese individuals with type 2 diabetes (Stienstra et al.,
These findings strongly support a model whereby danger signals generated in obesity are detected by the NLRP3-inflammasome that in turn promotes inflammation and the dysfunction of different organs involved in the control of glucose and lipid homeostasis (Figure
All together, these findings render the NLRP3 inflammasome as an attractive pharmacological target against the complications of obesity. In this multi-proteins complex, the easiest target is the caspase-1 since inhibitors already exist. The caspase-1 inhibitor Pralnacasan reduced body weight and improved insulin sensitivity of genetically obese
Despite the potential role of the NLRP3 inflammasome in obesity-induced inflammation and insulin resistance, it remains to determine whether its activation is a primary event in the disease that drives the inflammation. Further, the relative contribution of NLRP3 inflammasome to the development of inflammation in the metabolic tissues and in the different subset of cells of these tissues should be clarified. The role of other inflammasome complexes also deserves investigation since ablation of NLRP3 markedly reduced but did not totally abrogate caspase-1 activation in adipose tissue or liver of obese mice (Vandanmagsar et al.,
In conclusion, it is now recognized that the immune sensors described above (TLR, NOD, inflammasome) and others such as the pathogen-sensing kinase (PKR) (Nakamura et al.,
The Suppressor of cytokine signaling (SOCS) protein family also named Janus family kinase-binding (JAB) proteins or SSI (signal transducer and activator of transcription induced Stat inhibitor) includes eight members (SOCS1–7 and CIS), which possess a SH2 domain, and a SOCS-box domain controlling the degradation of interacting proteins. They are induced by several inflammatory cytokines and are involved in a negative feedback loop leading to the termination of cytokines action. At the molecular level, the SOCS proteins interact with the tyrosine kinases Janus-activated kinases (JAK) or directly with the receptor of some cytokines, thus blocking the tyrosine phosphorylation of the transcription factors STAT for review see Lebrun and Van Obberghen (
In obesity, inflammation leads to an up-regulation of SOCS proteins in hypothalamus, liver, muscles, and adipose tissue (Rieusset et al.,
The inhibition of SOCS proteins might thus be useful to prevent the development of obesity-induced insulin resistance. In agreement with such a possibility, heterozygous SOCS3 (SOCS3+/−) mice or mice with targeted invalidation of SOCS3 in the central nervous system (CNS) were protected against diet-induced obesity and associated insulin resistance (Howard et al.,
In summary, it appears to date that SOCS3 is mainly involved in the regulation of energy balance through the down-regulation of leptin signaling whereas several SOCS such as SOCS1/3/6/7 are involved in the regulation of the insulin sensitivity. Since SOCS proteins contribute to the development of diet-induced obesity and insulin resistance, their targeting could be open new avenues for the treatment of metabolic disorders. However, careful examination of the balance between pro-inflammatory and insulin sensitizing effects of future inhibitors of SOCS proteins will be needed.
The activity of both IκB-kinase β (IKKβ) and JNK is elevated in metabolic tissues in obesity, and these kinases are important nodes in the production of inflammatory mediators and in the desensitization of insulin signaling (Tanti and Jager,
ER stress occurs when the synthesis capacity of the ER is exceeded. In this case, the unfolded protein response (UPR) is activated in order to restore ER homeostasis. Three pathways are involved in the UPR, namely PERK (PKR-like eukaryotic initiation factor 2a), IRE-1 (inositol requiring enzyme 1), and ATF6 (activating transcription factor 6) pathways. If these mechanisms fail to restore proper ER homeostasis, cells undergo apoptosis (Xu et al.,
At the molecular level, one important mechanism by which IKKβ and JNK attenuate insulin signaling is the phosphorylation of IRS proteins on inhibitory serine phosphorylation sites (Figure
Several
The picture that emerges is that activation of these pathways in non-hematopoietic cells also participates in tissues inflammation and local or systemic insulin resistance. However, the consequences of IKKβ and JNK activation on the development of insulin resistance could totally differ and depend on the site of action, the level of expression and the impact on adiposity. Indeed, the activation of IKKβ/NF-κB in hepatocytes-induced liver inflammation and insulin resistance (Arkan et al.,
Several evidences suggest that activation of IKKβ and JNK pathways in the hypothalamus by over-nutrition contributes to energy imbalance and weight gain in addition to their role in the development of insulin resistance. At the molecular level, ER stress that develops in hypothalamus owing to an oversupply in nutriments activates the IKKβ/NF-κB pathway leading to local SOCS3 expression that interferes with both insulin and leptin signaling (Zhang et al.,
These studies support the idea that the over-activation of IKKβ/NF-κB and JNK pathways is a core mechanism that connects metabolic inflammation and insulin resistance both in peripheral tissues and in the CNS. This central role highlights IKKβ and JNK as potential pharmacological targets against the development of insulin resistance. In this regard, Shoelson and colleagues have shown that high-doses of salicylate and its derivative salsalate were able to inhibit IKKβ activity and to improve insulin sensitivity in obese mice (Donath and Shoelson,
The Extracellular signal-Regulated Kinases (ERK) 1/2 (also known as p44 and p42 MAP kinase) are activated by several growth factors but also by inflammatory cytokines. The activation of ERK1/2 requires the phosphorylation of both tyrosine and threonine residues located in a TEY sequence. This phosphorylation is mediated by the MAP kinase kinase (MAP2K) MEK. The activation of MEK also requires its phosphorylation by MAP kinase kinase kinase (MAP3K). Depending on the stimuli, different MAP3Ks are engaged to phosphorylate MEK. The activated ERK1/2 phosphorylates numerous substrates with serine or threonine residues close to a proline residue (Keshet and Seger,
The contribution of ERK pathway in the development of obesity and insulin resistance was first demonstrated by our study of ERK1-deficient mice (Bost et al.,
The pharmacological targeting of ERK1/2 against insulin resistance could have a series of drawbacks since they are involved in numerous biological processes. A possible alternative choice would be to target proteins which control ERK activity, specifically in response to inflammatory stresses which develop during obesity. In this regard, interesting candidates could be specific MAP3 kinases that are important in innate immune receptor signaling to MAP kinase activation (Symons et al.,
Among the different MAP3K that control ERK activity, our team recently identified the kinase Tpl2 (Tumor progression locus, MAP3K8) as a potential new player in adipose tissue dysfunction and inflammation (Jager et al.,
The discovery that metabolic diseases are associated with a low-grade inflammatory state has opened a new area of research to understand how inflammation develops and how it impact on metabolic pathways. It appears that a cross-talk between immune cells and metabolic cells plays a central role in the disturbance of metabolic homeostasis. High levels of dietary saturated fatty acids or of their metabolites can be detected by immune sensors such as TLR or inflammasome leading to the synthesis of inflammatory cytokines in different metabolic tissues. Dietary fat can also modify the intestinal microbiota that produces different inflammatory molecules leading to an inappropriate immune reaction. The inflammatory cytokines, saturated fatty acids, and LPS activate a network of signaling pathways that impinges on insulin signaling leading to alterations in metabolic cell functions. Hence, the importance of immune sensors and of different kinases suggests that new strategies targeting these proteins could be conceived to improve the metabolic complications of obesity.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Drs. Mireille Cormont and Yannick Le Marchand-Brustel for helpful suggestions and critical reading of the manuscript. We would like to apologize to colleagues for works which were not cited due to space limitation.
Author's work was supported by INSERM and CNRS and the University of Nice- Sophia Antipolis (France). Jean-François Tanti acknowledges support from ALFEDIAM-Abbott Laboratory, the French National Research Agency (grant ANR-2010-BLAN-1117-01) and the European Commission (Brussels, Belgium) (Contract LSHM-CT-2005–018734, Hepatic and Adipose Tissue and Functions in the Metabolic Syndrome, HEPADIP). Franck Ceppo is supported by a fellowship from the Region Provence Alpes-Cote d'Azur. Flavien Berthou is supported by the ANR grant ANR-2010-BLAN-1117-01.